EP2039360A1 - Administration directe non invasive d'opioïdes au système nerveux central - Google Patents

Administration directe non invasive d'opioïdes au système nerveux central Download PDF

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EP2039360A1
EP2039360A1 EP07116725A EP07116725A EP2039360A1 EP 2039360 A1 EP2039360 A1 EP 2039360A1 EP 07116725 A EP07116725 A EP 07116725A EP 07116725 A EP07116725 A EP 07116725A EP 2039360 A1 EP2039360 A1 EP 2039360A1
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Prior art keywords
opioid
formulation
formulation according
composition
mammal
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German (de)
English (en)
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Wolfgang Fleischer
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Euro Celtique SA
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Euro Celtique SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention concerns formulations and methods for the non-invasive direct delivery of opioids to the central nervous system (CNS). More particular, the invention concerns formulations comprising particulate carrier opioid compositions for the application on the skin/mucous membrane of a mammal and subsequent delivery of opioids directly to the central nervous system (CNS).
  • CNS central nervous system
  • routes using the gastrointestinal tract are even less preferred due to the fact that the substances are metabolized by the enzymes of the gastric, intestinal or rectal mucosa, the intestinal flora, or the liver (first-pass effect), all these involving a reduction in bioavailability and overall efficacy.
  • oral application is, despite these drawbacks, widely used due to its ease of application and convenience. For patients needing constant medication, e.g. patients suffering chronic severe pain, ease of application and convenience is of major importance.
  • direct application of the drug at the receptor site is advantageous with respect to accurate dosing, efficacy and reduced adverse side effects.
  • direct routes include the epidural and intrathekal routes of application.
  • the drug is injected in the epidural space located immediately outside of the protective sac which contains the spinal cord, whereas for an intrathekal application the drug is injected into the protective sac and into the CSF.
  • US 5 931 809 discloses a sustained release drug delivery system for epidural delivery of opioids.
  • the compositions are injected in the epidural space and release the drug from the lipid carrier system over a longer period of time as compared to epidural administration of the same drug in free (immediate release) form.
  • sustained-release formulations simplifies and reduces the overall cost of epidural analgesia by elimination of the need for continuous infusion, multiple bolus injections or emplacement of catheters, and also decreases the likelihood of infections.
  • the compositions still need to be injected and therefore safety issues and patient compliance issues are still not optimally addressed.
  • compositions and methods for the direct delivery of opioids to the central nervous system avoiding the disadvantages of invasive applications, such as the epidural or intrathekal application routes.
  • Liposomes are generally known drug or compound carriers and thus the application of medicaments in liposomal form has been the subject of investigation for quite some time.
  • An overview concerning the administration of compounds in liposomal form to the skin is provided by the review " Targeted delivery to the pilosebaceous unit via liposomes" (Lauer, A.C. et al. (1996), Advanced Drug Delivery Reviews, 18, 311-324 ). This review describes the physical-chemical characterisation of liposomal preparations and their therapeutic applications for the treatment of the pilosebaceous unit.
  • Compounds that have been investigated for delivery by liposomes include e.g. anti-cancer agents, peptides, enzymes, anti-asthmatic and anti-allergic compounds and antibiotics.
  • Liposomal opioid compositions are known for injection into the CSF or the blood system. These liposomal compositions prolong the release of the opioid and thereby reduce the application frequency. The route of application is again invasive.
  • US 5 931 809 discloses controlled release liposomal opioid composition for epidural injection. These compositions and respective method of application are invasive and although the application frequency is reduced, suffer still from safety and compliance issues.
  • US 0 300 806 discloses release controlled injectable liposomal opioid compositions. The compositions are injected into the blood system. The composition and respective method of application still suffer from the drawbacks of the systemic route of application as well as from safety and compliance issues.
  • the objective of the invention is to provide formulations for the direct delivery of actives, in particular opioids to the CNS avoiding invasive steps.
  • the object of the invention is further to treat mammals, preferably humans with actives such as opioids via direct non invasive delivery of actives such as opioids to the CNS.
  • the invention is directed to formulations comprising particulate carrier active compositions (such as a particulate carrier opioid composition).
  • the invention is further directed to the use of the inventive formulations and in particular the particulate carrier active- e.g. opioid-compositions for the manufacture of a medicament for the treatment of mammals, preferably humans with actives such as opioids via direct non invasive delivery of actives such as opioids to the CNS.
  • the invention is further directed to a method of treating pain in mammals, preferably humans, comprising the treatment with the inventive formulations comprising particulate carrier active- e.g. opioid-compositions thereby achieving direct non invasive delivery of actives such as opioids to the CNS.
  • particulate carrier active e.g. opioid-compositions
  • the inventive formulations comprise particulate carrier active- e.g. opioid-compositions which comprise at least one active such as an opioid substantially enclosed in a particulate carrier composition wherein said carrier composition is capable of delivering the at least one active such as an opioid to cerebral nerves (cranial nerves) or the spinal cord upon application of said formulations comprising said particulate carrier active- e.g. opioid-compositions to the mammals surface skin or mucous membrane, at the site of said cerebral nerves or the spinal cord, across the respective cell membrane and/or cutaneous barriers between said cerebral nerves or the spinal cord and the external surface of said skin, or mucous membrane.
  • particulate carrier active- e.g. opioid-compositions which comprise at least one active such as an opioid substantially enclosed in a particulate carrier composition wherein said carrier composition is capable of delivering the at least one active such as an opioid to cerebral nerves (cranial nerves) or the spinal cord upon application of said formulations comprising said particulate carrier active- e.g. opioid-compositions to
  • the olfactory nerve is the first of twelve cranial nerves.
  • the olfactory nerve is the shortest of all the twelve cranial nerves and one of the only two cranial nerves (the other being the optic nerve which is also a suitable target for the present invention) that do not join with the brainstem.
  • the olfactory nerve consists of a collection of sensory nerve fibers that extend down from the olfactory bulb and pass through the many openings of the cribriform plate, a sieve-like structure.
  • the specialized olfactory receptor neurons of the olfactory nerve are located in the olfactory mucosa of the upper parts of the nasal cavity.
  • the olfactory mucosa is an organ made up of the olfactory epithelium and the mucosa, or mucus secreting glands, behind the epithelium.
  • the mucus protects the olfactory epithelium and allows odors to dissolve so that they can be detected by olfactory receptor neurons.
  • the olfactory mucosa is located on the roof of the nasal cavity above and behind the nostrils.
  • the olfactory epithelium consists of three basic cell types: olfactory receptor neurons; sustentacular cells, a type of supporting cell; and basal cells, the stem cells that continuously give rise to new olfactory receptor neurons and sustentacular cells.
  • An olfactory receptor neuron also called an olfactory sensory neuron, is the primary transduction cell for olfaction in the olfactory system.
  • Humans have about 40 mullion olfactory receptor neurons.
  • the cells are bipolar neurons with a dendrite facing the interior space of the nasal cavity and an axon that travels along the olfactory nerve to the olfactory bulb.
  • the particular carrier composition can be delivered directly to the nerve substantially without passing any cutaneous barriers.
  • the inventive particulate carrier compositions directly deliver actives such as opioids to the central nervous system (CNS) across cutaneous barriers into cerebral nerves as e.g. the olfactory nerve or the spinal cord.
  • the opioids are thereby delivered to the CNS substantially avoiding the systemic distribution of the opioids throughout the body.
  • the application is non-invasive and therefore safe and easy to use.
  • the application also substantially avoids systemic distribution of the opioid(s), and therefore allows accurate and minimal dosing and reduces adverse side effects.
  • the present invention is also directed to any treatment of mammals, preferably humans, by delivering opioids to the CNS via celebral nerves or the spinal cord, in particular via celebral nerves such as the olefactory nerve.
  • the invention is particularly useful for treatments that require constant medication with opioids that are predominantly supposed to react with receptors at the site of the CNS, e.g. the treatment of chronic severe pain.
  • the present invention is further directed to the manufacture of medicaments for the direct delivery to the cerebral nerves or the spinal cord, in particular the cerebral nerves such as the olfactory nerve.
  • direct delivery means delivery of substances to the CNS substantially avoiding a systemic distribution of the substance prior to delivery to the CNS, or the cerebral nerves e.g. epidural or intrathekal application or the non-invasive application according to the invention.
  • non-invasive means without opening a pathway for delivery through a membrane such as skin, by use of apparative means, e.g. by use of injection or the like.
  • particulate carrier composition includes any particulate carrier composition suitable to facilitate the transport of substances e.g. across cutaneous barriers.
  • the preferred particulate carriers are liposomes.
  • articulate carrier opioid compositions include any particulate carrier composition suitable to transport substances across cutaneous barriers comprising at least one opioid.
  • the preferred particulate carriers are liposomes.
  • opioid is considered to include opioid agonists and opioid antagonists, mixed opioid antagonists/agonists as well as mixtures thereof.
  • opioid includes opioids in the form of the free base as well as pharmaceutically acceptable salts thereof.
  • target nerve tissue and “target nerve” are used interchangeable and include nerve tissue that may transport the opioid(s) to the CNS along its nerve pathway.
  • Preferred “target nerve tissues” are nerves that run close to the body surface, Suitable nerves are cerebral nerves such as the nervus olefactorius, nervus opticus and nervus acusticus. Preferred is the nervus olefactorius.
  • cutaneous barriers include the skin, parts of the skin, membranes, tissue and mucous membranes of a mammal, preferably a human. These cutaneous barriers are between the target nerve tissue and the surface of the skin or mucous membrane of the mammal the inventive compositions are applied to.
  • surface skin or mucous membrane means those skins or mucous membranes of a mamma! that form the body surface of the mammal and arc exposed to outer environment.
  • the distance between the target nerve tissue and the surface of the skin or mucous membrane is as short as possible.
  • surface skin or mucous membrane at the site of the target nerve tissue means the surface skin or mucous membrane closest to the target nerve tissue.
  • Preferred is the olefactory mucosa.
  • inventive particulate carrier active compositions comprise at least one opioid.
  • opioid agonists comprise all compounds that belong to class NO2A of opioid analgesics according to the ATC Classification of the WHO.
  • an opioid agonist is selected from the group of morphine, oxycodone, hydromorphone, oxymorphone, buprenorphine, fentanyl, afentanyl, sulfentanyl, propoxyphene, nicomorphine, dihydrocodeine, diamorphine, papaveretum, codeine, ethylmorphine, phenylpiperidine and derivates thereof, methadone, dextropropoxyphene, pentazocine, tilidine, tramadol and hydrocodone.
  • analgesic examples include meperidine, alphaprodine, anileridine, dextromoramide, metopone, levorphanol, phenazocine, etoheptazine, propiram, profadol, phenampromide, thiambuten, pholcodeine, codeine, dihydrocodeinon, 3-trans-dimethylamino-4-phenyl-4-trans-carbethoxy-A'-cyclohexen, 3-dimethylamino-0-(4-methoxyphenyl-carbamoyl)-propiophenone oxime, (-) ⁇ -2'-hydroxy-2, 9-dimethyl-5-phenyl-6, 7-benzomorphane, (-)2'-hydroxy-2-(3-methyl-2-butenyl)-9-methyl-5-phenyl-6, 7-benzomorphane, pirinitramide, (-) ⁇ -5,9-diethyl-2'
  • Especially preferred analgesically effective opiod agonists are, hydromorphone, morphine, buprenorphin, fentanyl, afentanyl and sulfentanyl, levomethadone, oxycodone, piritramideor the pharmaceutically acceptable salts thereof.
  • opioid antagonists comprise such compounds that counteract opioid agonists. Such compounds can also be found in the ATC Classification of the WHO. According to the invention, compounds are preferred that upon application in accordance with the invention decrease the side effects, the habituation effects and the addictive potential caused by the opioid agonists.
  • Antagonists can comprise among others, naltrexone, naloxone, nalmefene, nalorphine, nalbuphine, naloxoneazinen, methylnaltrexone, ketylcyclazocine, norbinaltorphimine, naltrindol, 6- ⁇ -naloxol and 6- ⁇ -naltrexol or the pharmaceutically acceptable salts thereof.
  • Especially preferred antagonists comprise naltrexone, nalmefene and naloxone or the pharmaceutically acceptable salts thereof. Most preferred is naloxone or a pharmaceutically acceptable salt thereof.
  • inventive particulate carrier opioid compositions comprise at least one opioid, e.g. an opioid agonist or an opioid antagonist.
  • inventive particulate carrier opioid compositions may also comprise the combination of an opioid agonists and an opioid antagonist to reduce side effects and the risk of abuse.
  • the opioid agonist may be combined with one or more actives, in particular selected from the group of antidepressants.
  • Suitable antidepressants are moclobemide, tranylcypromine, amitriptyline, amitriptylinoxide, clomipramine, doxepine, maprotiline, lofepramine, trimipramine, dosulepine, imipramine, opiramol, mianserine, nortriptyline, dibenzepine, desipramine, mirtazapine, fluoxetine, fluroxamine, citalopram, paroxetine, sertraline, tryptophane, reboxetine, ulpirid, nefazodone, tranzodone, venlafaxine, viloxazine or the pharmaceutically acceptable salts thereof.
  • the opioid may be combined with any active suitable for delivery to the CNS.
  • the opioid may be substituted by any other active suitable for delivery to the CNS.
  • the afore-mentioned active agents may also be used in the form of their pharmaceutically acceptable salts.
  • Preferred salts may be acid addition salts such as the hydrochloride salt. Typical examples are oxycodone hydrochloride and naloxone hydrochloride.
  • the inventive formulations comprise at least one particulate carrier composition.
  • Preferred particulate carriers are liposomes.
  • the known prior art methods for forming liposome structures can generally be used in the context of the invention. Broadly, these methods comprise mechanical agitation of a suitable mixture containing the membrane-forming substance and water or an aqueous solution. Filtration through suitable membranes is preferred in order to form a substantially uniform liposome size.
  • liposome-forming systems comprising lecithin are preferred.
  • Such systems can comprise hydrogenated soy bean lecithin besides cholesterol and disodium succinatehexahydrate. It is presently specifically preferred to use hydrogenated soy bean lecithin as the sole membrane-forming agent.
  • Commercially available products such as Phospholipon® 90 H (Aventis, Germany) or Lipoid S100-3 (Lipoid GmbH, Germany) are also preferred.
  • phospholipid-based liposomes may also be generally used for production of liposomes that transport their cargo through the skin. According to this review, the use of non-ionic liposomes, which can be formed with phosphatidylcholin, is also an option.
  • Other components that may be used for the formation of micelles are also known to the person skilled in the art and may be used for the production of compositions according to the invention.
  • the average size of the particulate carrier in particular liposomes according to this invention can vary and varies preferably from about 1 nm to about 300 nm. Liposomes or particulate carriers having diameters in the range of about 50 nm and 200 nm are most preferred. Liposomes having diameters in the range of about 50 nm and 200 nm are most preferred.
  • particulate carriers are generally prepared as known in the art.
  • microspheres which are used to deliver a very wide range of therapeutic or cosmetic agents, are made as described for example in WO 95/15118 .
  • Nanoparticles may in some cases be used, provided that they can be loaded with a sufficient amount of opioid. They can be prepared according to the methods known in the art.
  • PLD pulse laser deposition
  • a further suitable delivery system employs Large Porous Particles as disclosed by David A. Edwards et al. in “Large Porous Particles for Pulmonary Drug Delivery” (Science, 20. June 1997, Vol. 276, p 1868-1871 ).
  • inventive formulations comprise a particulate carrier composition comprising at least one opioid and/or optionally other actives as described above, and optionally additional adjuvants.
  • the amount of active such as an opioid in an inventive formulation will be determined by the desired effect on the one hand and the carrying capacity of the carrier composition for the actives such as an opioid and the maximum concentration of the carrier composition in the Formulation on the other hand.
  • the amount of opioid(s) in an inventive carrier composition can range in concentrations between the lower limit of effectiveness of the opioid(s) and the maximum loading of the opioid(s) in the respective carrier composition and at a maximum concentration of the carrier composition in the formulation. It is understood that the opioid(s) are present in the inventive compositions in a pharmaceutically sufficient amount.
  • the preferred formulation comprises for example from 5 to 20 % w/w opioid, or from 10 to 15 % w/w opioid, in particular about 10 % w/w opioid, based on the weight of the free base, and is for example administered in doses of 10 to 1000 ⁇ g, or 10 to 100 ⁇ g of the formulation.
  • the opioid is preferably administered in doses of 1/10 to 1/1000 of the respective required intravenous dose.
  • hydromorphone formulations are administered in dose ranges of 0,2 x 10 -3 mg - 100 mg or 0,4 x 10 -3 mg - 50 mg or 2 x 10 -3 mg - 10mg or 0,2 x 10 -3 mg - 0,19 mg hydromorphone.
  • morphine formations are administered in dose ranges of 1 x 10 -3 mg - 400 mg or 2 x 10 -3 mg - 200 mg or 1 x 10 -2 mg - 40 mg or 1 x 10 -2 mg - 0,9 mg morphine.
  • buprenorphine formations are administered in dose ranges of 0,003 x 10 -3 mg - 0,3 mg or 0,006 x 10 -3 mg - 0,15 mg or 0,03 x 10 -3 mg - 0,03 mg or 0,003 x 10 -3 - 0,0029 mg buprenorphine.
  • fentanyl formations are administered in dose ranges of 0,005 x 10 -3 mg - 0,5 mg or 0,01 x 10 -3 mg - 0,25 mg or 0,05 x 10 -3 mg - 0,05 mg or 0,005 x 10 -3 mg - 0,0049 mg fentanyl.
  • oxycodon administered in dose ranges of 1 x 10 -3 mg - 200 mg or 2 x 10 -3 mg - 100 mg or I x 10 -2 mg - 20 mg or 1 x 10 -3 mg - 0,9 mg oxycodon.
  • sulfentanyl administered in dose ranges of 0,0005 x 10 -3 mg - 0,5 mg or 0,001 x 10 -3 mg - 0,25 mg or 0,0005 x 10 -2 mg - 0,05 mg or 0,0005 x 10 -3 mg - 0,00049 mg sulfentanyl.
  • One preferred method for producing the invention's liposomal opioid composition can generally be described as follows:
  • the lipid membrane-forming components e. g. lecithin
  • a suitable solvent such as chloroform or a 2: 1 mixture of methanol and chloroform
  • a lipid film is then produced on a sterile high surface substrate, such as glass beads, by controlled evaporation of the solvent.
  • a sterile high surface substrate such as glass beads
  • An aqueous system is prepared from electrolyte components and the opioid(s) and/or other actives to be incorporated in the liposome composition.
  • Such an aqueous system can e. g. comprise 10 mmol/l sodium hydrogen phosphate and 0.9 % sodium chloride, at pH 7.4; the aqueous system will further comprise the desired amount of actives/opioid(s). Often, the aqueous system will comprise an excess amount of the opioid(s) and/or other actives.
  • the liposomes are generally formed by agitating said aqueous system in the presence of said film formed by the lipid components. At this stage, further additives can be added to improve liposome formation; e. g. sodium cholate. Liposome formation is preferably influenced by mechanical action such as pressure filtration through e. g. polycarbonate membranes, or centrifuging. Generally, the raw liposome dispersion will be washed, e. g. with electrolyte solution as used in preparing the above-described solution of the active agent.
  • liposomes with the required size distribution When liposomes with the required size distribution have been obtained and washed, they can be freeze dried and/or redispersed in a suitable carrier liquid at a suitable concentration to provide a liquid sprayable formulation.
  • inventive formulations can also contain other customary agents, including adjuvants and additives, antioxidants, conserving agents or consistency-forming agents such as viscosity-adjusting additives, emulgators, etc.
  • adjuvants and additives include e.g. DMSO or compounds selected from the group of fatty acids, fatty acid esters and fatty alcohols.
  • Preferred formulations are in the form of a liquid sprayable formulation.
  • the formulation may contain a dry particulate composition.
  • the formulation is administered as aerosol or spray formulation.
  • an aerosol which is e.g. provided by a nebulizer device.
  • a nebulizer device usually contain a pressurized mixture of the formulation, liquid or dry, and a propellant. By actuation of the device a predetermined amount of a mixture is released from the device. Due to the sudden pressure decrease the propellant evaporates and the formulation is finely distributed/nebulized.
  • nebulized formulations are e.g. capable of traveling deeply into the nasal passage and reaching the olefactory mucosa in the upper part of the nasal passage.
  • a particularly preferred embodiment of the invention is a formulation comprising a liposome composition comprising at least one opioid.
  • Such compositions comprise Phospholipon® 90 H (Aventis, Germany) as liposome-forming material.
  • Phospholipon® 90 H is a 90% hydrogenated phosphatidylcholin preparation which is more storage-stable than unhydrogenated phosphatidylcholin preparations.
  • Suitable cerebral nerves are those that run close to the body surface.
  • the nervus olfactorius, nervus opticus and nervus accusticus are suitable.
  • the nervus olefactorius is preferred.
  • the inventive liposomal opioid formulation is applied to the skin or mucous membrane located at the site of the respective target nerve tissue, preferably the olefactory mucosa.
  • the liposomal carriers loaded with the opioid(s) diffuse through the respective cutaneous barriers/membranes to the target nerves.
  • cutanous/membrane barriers vary with the target nerve tissue and the respective place of application on the surface skin or mucous membrane, however, preferred is the olefactory mucosa.
  • a nebulizer device For the delivery to the olfactory mucose according to one embodiment of the invention, a nebulizer device is used.
  • usefull are also devices that exploits the body's natural reflex that isolates the nasal circuit from the lungs during exhalation against a resistance.
  • the exhaled air actuates the delivery device, the airflow created by exhalation then carries the spray doplets into the nose and into the posterior nasal passage beyond the nasal valve, allowing deposition of active substance in the region of the olefactory bulb.
  • the process of breathing-out automatically closes the nasal cavity, removing the risk of distribution to the lungs.
  • the fentanyl citrate solution is then added to the lipid film in the flask and the mixture is shaken until the film is dissolved.
  • the resulting raw liposome formulation is then subjected to a high pressure filtering step through a polycarbonate membrane to produce small, unilamellar liposomes with high amounts of encapsulated fentanyl citrate and a size form 50 to 200 nm.
  • the high pressure filtering step can alternatively be employed after any subsequent washing step or instead high pressure homogenization or other prior art methods known to provide small uniform sized liposomes can be employed.
  • the liposome composition is then separated from the hydrated lipids in the flask.
  • the product is centrifuged and the supernatant liquid is discarded.
  • the saccharose solution is added ad 12 ml and the product is again centrifuged. Afterwards the supernatant liquid is again discarded.
  • a further washing step using the saccharose solution or the sodium chloride buffer solution could be carried out.
  • the liposome composition can be freeze dried according to standard procedures.
  • the resulting raw liposome formulation is then subject to a high pressure filtering step through a polycarbonate membrane to form unilamellar liposomes with a size from 50 to 200 nm .
  • the high pressure filtering step can alternatively be employed after any subsequent washing step or instead high pressure homogenization or other prior art methods known to provide small uniform sized liposomes can be employed.
  • the product is centrifuged and the supernatant liquid is discarded.
  • the liposome composition can be freeze dried according to standard procedures.
  • the liposome compositions of examples I and II are mixed with a liquid carriers selected from the group of water, aqueous buffer solvents, mixtures of water and aqueous buffer solutions with polar organic solvents as e.g. ethanol to form formulations with different concentrations of fentanyl.
  • a liquid carriers selected from the group of water, aqueous buffer solvents, mixtures of water and aqueous buffer solutions with polar organic solvents as e.g. ethanol
  • polar organic solvents as e.g. ethanol
  • the formulation can be administered in 20 ⁇ g doses comprising an amount of fentanyl citrate or hydromorphone hydrochloride corresponding to 2 ⁇ g fentanyl or hydromorphone free base.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9650338B1 (en) 2016-07-29 2017-05-16 VDM Biochemicals, Inc. Opioid antagonist compounds and methods of making and using

Citations (6)

* Cited by examiner, † Cited by third party
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